頭孢泊肟酯牛至油納米乳的研制
發(fā)布時間：2019-07-05 14:13
【摘要】：目的:為研究頭孢泊肟酯與牛至油在納米水平的聯(lián)合藥效,首次制備頭孢泊肟酯牛至油納米乳(cefpodoxime proxetil and origanum oil nanoemulsion,CFP-OR-NE),并進行藥物穩(wěn)定性、有效性、安全性評價,為治療致病性大腸桿菌病和賽鴿仙臺沙門氏菌病提供一種安全有效的新型口服藥物。方法:(1)CFP-OR-NE處方篩選:采用相轉(zhuǎn)變法篩選初步處方。通過加水滴定至相變點并結(jié)合偽三元相圖的繪制,篩選CFP-OR-NE的初步處方;采用多指標正交試驗法篩選CFP-OR-NE最優(yōu)處方。以L9(34)正交表設(shè)計試驗,以抑菌圈直徑和納米乳穩(wěn)定常數(shù)Ke為考察指標,選擇頭孢泊肟酯和牛至油質(zhì)量分數(shù)比(A)、納米乳水相pH值(B)、乳化溫度(C)作為考察因素,篩選頭孢泊肟酯牛至油納米乳最優(yōu)處方。(2)CFP-OR-NE的質(zhì)量評價:以多波長紫外分光光度法建立CFP-OR-NE有效成分含量測定方法,進行回收率試驗、進樣重復(fù)性試驗及日內(nèi)日間精密度試驗;穩(wěn)定性試驗中考察了CFP-OR-NE結(jié)構(gòu)類型、形態(tài)觀察、粒徑分布及Zeta電位等指標,長期試驗中分別建立兩者含量-時間回歸方程,計算藥物有效期。(3)CFP-OR-NE的體外抑菌試驗:通過微量肉湯稀釋法測定CFP-OR-NE對多種革蘭氏陰性菌(G+)和革蘭氏陽性菌(G-)的最低抑菌濃度(minimum inhibitory concentration,MIC)和最低殺菌濃度(minimal bactericidal concentration,MBC)。(4)CFP-OR-NE的安全性評價:通過最大耐受計量法測定小鼠經(jīng)口急性毒性最大耐受劑量并對其進行組織病理學(xué)檢查,確定CFP-OR-NE是否具有肝毒性、腎毒性、腸毒性。結(jié)果:(1)CFP-OR-NE處方篩選:CFP-OR-NE初步處方各組分質(zhì)量分數(shù)為:CFP1.5%、OR1.5%、EL-40 22.51%、1,2-丙二醇1.13%、蒸餾水73.36%;CFP-OR-NE針對致病性大腸桿菌、沙門氏菌最優(yōu)處方為CFP 0.33%、OR 2.67%、1,2-丙二醇1.13%、EL-40 22.51%、蒸餾水73.36%,納米乳pH值為6.17。(2)質(zhì)量評價:建立了CFP-ORNE藥物含量測定方法,CFP測定的檢測波長和參比波長分別為263nm和289.8nm,OR測定的組合波長為261.6 nm、273.2 nm、284.4 nm。在1~100μg/mL范圍內(nèi),CFP和OR線性關(guān)系均良好(r2=0.999 22;r2=0.999 70);回收率試驗:9個試驗號的回收率均符合70%~110%的要求,CFP的RSD范圍在0.4~8.95%之間,OR的RSD范圍在0.26~5.57%之間;進樣重復(fù)性試驗:各試驗號CFP及OR測定的RSD均小于0.6%,進樣重復(fù)性良好;日內(nèi)日間精密度試驗:CFP-OR-NE中CFP和OR測定的日內(nèi)、日間精密度RSD均小于5%,日內(nèi)日間精密度良好;CFP-OR-NE為水包油型淡黃色透明液體,形態(tài)觀察CFPOR-NE乳滴呈圓球形,平均粒徑為18.94 nm,多分散系數(shù)0.258,粒徑大小均一且分布范圍較窄。在環(huán)境溫度25℃條件下,稀釋5倍后的平均pH值為6.39,zeta電位是(-9.96±6.35)mV,加速、離心、光照、溫度梯度實驗、長期試驗結(jié)果均無分層、絮凝、轉(zhuǎn)型、破乳、酸敗等現(xiàn)象,測定CFP-OR-NE有效期為21個月。(3)體外抑菌試驗:與OR原料藥、頭孢克肟(cefixime,CFM)原料藥相比,CFP-OR-NE的MIC及MBC差異顯著(P0.05)。(4)安全性評價:最大耐受計量法測定小鼠經(jīng)口急性毒性最大耐受劑量大于1 800 mg/kg,組織病理學(xué)檢查CFP-OR-NE無腎臟毒性和腸毒性,試驗組肝臟,輕微出血,少許細胞變性壞死,分界不清,但未引起小鼠死亡。結(jié)論:研制出CFP-OR-NE并建立了藥物含量測定方法,質(zhì)量評價符合規(guī)定要求;體外抑菌試驗表明CFP-OR-NE對臨床常見G+和G-的抑菌和殺菌效果優(yōu)于同為三代頭孢菌素的CFM;MTD試驗表明CFP-OR-NE為低毒藥物,組織病理學(xué)檢查無腎、腸毒性。
[Abstract]:Objective: To study the effect of cefpodoxime proxetil (Cefpodoxime proxetil) and bovine-to-oil at nanometer level, and to prepare cefpodoxime and oil nanoemulsion (CFP-OR-NE) for the first time, and to evaluate the stability, effectiveness and safety of cefpodoxime proxetil (CFP-OR-NE). In ord to provide a safe and effective novel oral medicine for treating that pathogenic E. coli and the salmonellosis. Methods: (1) CFP-OR-NE prescription screening: a phase transition method was used to screen the initial prescription. The initial formulation of CFP-OR-NE was selected by titration of water to the phase change point and the pseudo-ternary phase diagram, and the optimal formulation of the CFP-OR-NE was selected by the multi-index orthogonal test method. The experiment was designed with L9 (34) orthogonal table, and the diameter of the bacteriostatic ring and the stability constant of the nano-emulsion Ke were selected as the study index, and the ratio (A), the pH value (B) of the nano-emulsion water phase and the emulsification temperature (C) were selected as the factors of the investigation. The optimal formulation of the cefpodoxime proxetil to the oil nanoemulsion is screened. (2) The quality evaluation of CFP-OR-NE: The determination method of the effective component of CFP-OR-NE was established by multi-wavelength ultraviolet spectrophotometry, the recovery test, the injection repeatability test and the day-day precision test were carried out, and the structure type and morphology of the CFP-OR-NE were investigated in the stability test. In the long-term test, the content-time regression equation was established, and the validity of the drug was calculated. (3) In vitro antibacterial test of CFP-OR-NE: the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of CFP-OR-NE on a variety of Gram-negative bacteria (G +) and gram-positive bacteria (G-) were determined by a microbroth dilution method. (4) Safety evaluation of CFP-OR-NE: The maximum tolerated dose of the oral acute toxicity of the mouse was determined by the maximum tolerance measurement method and the histopathological examination was performed to determine whether the CFP-OR-NE had hepatotoxicity, renal toxicity, and intestinal toxicity. Results: (1) CFP-OR-NE prescription was selected: CFP1.5%, OR1.5%, EL-40 22.51%, 1,2-propanediol 1.13%, distilled water 73.36%, CFP-OR-NE for pathogenic E. coli, the optimal prescription of Salmonella was CFP 0.33%, OR 2.67%, 1,2-propanediol 1.13%, EL-40 22.51%, The distilled water was 73.36%, and the pH value of the nano-emulsion was 6.17. (2) Quality evaluation: The method for determination of the content of CFP-ORNE was established. The detection wavelength and reference wavelength of CFP were 263 nm and 289.8 nm, respectively, and the combined wavelength was 261.6 nm, 273.2 nm and 284.4 nm respectively. In the range of 1 to 100 & mu; g/ mL, the linear relationship between the CFP and the OR was good (r2 = 0.999 22; r2 = 0.999 70); the recovery test: the recovery rate of the 9 test numbers met the requirements of 70% to 110%, the RSD of the CFP was between 0.4 and 8.95%, the RSD of the OR was between 0.26 and 5.57%, and the injection repeatability test: The RSD of each test number CFP and OR was less than 0.6% and the injection repeatability was good; intra-day precision test: the day-day precision RSD was less than 5% within the day of the CFP and OR measurement in the CFP-OR-NE, and the intra-day precision was good; and the CFP-OR-NE is an oil-in-water type light yellow transparent liquid, The form of CFPOR-NE emulsion is spherical, the average particle size is 18.94 nm, the polydispersity coefficient is 0.258, the particle size is uniform and the distribution range is narrow. The mean pH value after 5-fold dilution at ambient temperature was 6.39, the zeta potential was (-9.96-6.35) mV, acceleration, centrifugation, illumination, temperature gradient experiment, and the results of long-term test were no delamination, flocculation, transformation, demulsification, rancidity, etc., and the validity period of CFP-OR-NE was 21 months. (3) In vitro antibacterial test: Compared with the drug substance of OR drug substance and cefixime (CFM), the MICs and MBC of CFP-OR-NE were significant (P0.05). (4) Safety evaluation: The maximum tolerated dose of the oral acute toxicity in mice was more than 1 800 mg/ kg, and the histopathological examination of CFP-OR-NE had no renal toxicity and intestinal toxicity. Conclusion: CFP-OR-NE has been developed and the drug content determination method is established, and the quality evaluation is in accordance with the specified requirements; in vitro antibacterial test shows that the antibacterial and bactericidal effect of CFP-OR-NE on the clinical common G + and G-is better than that of the three-generation cephalosporin; and the MTD test shows that the CFP-OR-NE is a low-toxic medicine, Histopathological examination showed no renal or intestinal toxicity.
【學(xué)位授予單位】：西北農(nóng)林科技大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：S859.79
本文編號：2510581
[Abstract]:Objective: To study the effect of cefpodoxime proxetil (Cefpodoxime proxetil) and bovine-to-oil at nanometer level, and to prepare cefpodoxime and oil nanoemulsion (CFP-OR-NE) for the first time, and to evaluate the stability, effectiveness and safety of cefpodoxime proxetil (CFP-OR-NE). In ord to provide a safe and effective novel oral medicine for treating that pathogenic E. coli and the salmonellosis. Methods: (1) CFP-OR-NE prescription screening: a phase transition method was used to screen the initial prescription. The initial formulation of CFP-OR-NE was selected by titration of water to the phase change point and the pseudo-ternary phase diagram, and the optimal formulation of the CFP-OR-NE was selected by the multi-index orthogonal test method. The experiment was designed with L9 (34) orthogonal table, and the diameter of the bacteriostatic ring and the stability constant of the nano-emulsion Ke were selected as the study index, and the ratio (A), the pH value (B) of the nano-emulsion water phase and the emulsification temperature (C) were selected as the factors of the investigation. The optimal formulation of the cefpodoxime proxetil to the oil nanoemulsion is screened. (2) The quality evaluation of CFP-OR-NE: The determination method of the effective component of CFP-OR-NE was established by multi-wavelength ultraviolet spectrophotometry, the recovery test, the injection repeatability test and the day-day precision test were carried out, and the structure type and morphology of the CFP-OR-NE were investigated in the stability test. In the long-term test, the content-time regression equation was established, and the validity of the drug was calculated. (3) In vitro antibacterial test of CFP-OR-NE: the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of CFP-OR-NE on a variety of Gram-negative bacteria (G +) and gram-positive bacteria (G-) were determined by a microbroth dilution method. (4) Safety evaluation of CFP-OR-NE: The maximum tolerated dose of the oral acute toxicity of the mouse was determined by the maximum tolerance measurement method and the histopathological examination was performed to determine whether the CFP-OR-NE had hepatotoxicity, renal toxicity, and intestinal toxicity. Results: (1) CFP-OR-NE prescription was selected: CFP1.5%, OR1.5%, EL-40 22.51%, 1,2-propanediol 1.13%, distilled water 73.36%, CFP-OR-NE for pathogenic E. coli, the optimal prescription of Salmonella was CFP 0.33%, OR 2.67%, 1,2-propanediol 1.13%, EL-40 22.51%, The distilled water was 73.36%, and the pH value of the nano-emulsion was 6.17. (2) Quality evaluation: The method for determination of the content of CFP-ORNE was established. The detection wavelength and reference wavelength of CFP were 263 nm and 289.8 nm, respectively, and the combined wavelength was 261.6 nm, 273.2 nm and 284.4 nm respectively. In the range of 1 to 100 & mu; g/ mL, the linear relationship between the CFP and the OR was good (r2 = 0.999 22; r2 = 0.999 70); the recovery test: the recovery rate of the 9 test numbers met the requirements of 70% to 110%, the RSD of the CFP was between 0.4 and 8.95%, the RSD of the OR was between 0.26 and 5.57%, and the injection repeatability test: The RSD of each test number CFP and OR was less than 0.6% and the injection repeatability was good; intra-day precision test: the day-day precision RSD was less than 5% within the day of the CFP and OR measurement in the CFP-OR-NE, and the intra-day precision was good; and the CFP-OR-NE is an oil-in-water type light yellow transparent liquid, The form of CFPOR-NE emulsion is spherical, the average particle size is 18.94 nm, the polydispersity coefficient is 0.258, the particle size is uniform and the distribution range is narrow. The mean pH value after 5-fold dilution at ambient temperature was 6.39, the zeta potential was (-9.96-6.35) mV, acceleration, centrifugation, illumination, temperature gradient experiment, and the results of long-term test were no delamination, flocculation, transformation, demulsification, rancidity, etc., and the validity period of CFP-OR-NE was 21 months. (3) In vitro antibacterial test: Compared with the drug substance of OR drug substance and cefixime (CFM), the MICs and MBC of CFP-OR-NE were significant (P0.05). (4) Safety evaluation: The maximum tolerated dose of the oral acute toxicity in mice was more than 1 800 mg/ kg, and the histopathological examination of CFP-OR-NE had no renal toxicity and intestinal toxicity. Conclusion: CFP-OR-NE has been developed and the drug content determination method is established, and the quality evaluation is in accordance with the specified requirements; in vitro antibacterial test shows that the antibacterial and bactericidal effect of CFP-OR-NE on the clinical common G + and G-is better than that of the three-generation cephalosporin; and the MTD test shows that the CFP-OR-NE is a low-toxic medicine, Histopathological examination showed no renal or intestinal toxicity.
【學(xué)位授予單位】：西北農(nóng)林科技大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：S859.79
【參考文獻】
相關(guān)期刊論文 前1條
1 張濤;顧起有;楊后貴;郭楊慶;;頭孢泊肟酯與頭孢克肟治療急性細菌性感染隨機對照研究[J];海峽藥學(xué);2006年02期
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